Computational tools are becoming increasingly important to integrate the wealth of structural data with more traditional lead optimization techniques. Amongst them, virtual screening is bringing a more cost-effective approach to drug discovery by using high-performance computing to analyze chemical databases and prioritize compounds for synthesis and assay. Despite the definite potential of some natural products, there is still a problem associated with the targeting selection due to the multitude and chemical diversity of natural products. To overcome this challenge modern computer-aided screening techniques such as biological target modeling coupled together with virtual screening has been extensively used. Further, virtual screening provides enough reliable structural information about the target, or compounds that bind to various biomolecules.
Receptor-based virtual screening (REVS) starts with a 3-D structure of a target protein and a ligand followed by docking to identify potential lead candidates, Docking and scoring algorithms generate subsets of a compound collection with a higher affinity against a target by predicting their binding mode (by docking) and affinity (by free energy). The docking algorithms deal with the prediction of ligand conformation and orientation within the targeted active site of the receptor. Some of the most widely used docking programs in high through put searches are DOCK, FlexX, GOLD, Glide, ICM, FRED and AutoDock.
The aim of this study is to demonstrate the strategy of utilizing computer-aided (in silica) receptor based virtual screening for improved acetylcholinesterase (AchE) inhibitors such as meroterpenoids.
The effective control and protection of desirable plant life is possible through the use of chemicals formulated to provide protection as selective insecticides and pesticides. However, all requirements for effectiveness and selectivity among pesticides have not been satisfied. There are still many demands to satisfy among agriculturalists and others, either for more effective pesticides with selectivity comparable to old pesticides, or for pesticides with a different selectivity.
Enzyme inhibitors are important class of molecules that used as drugs and pesticides. The enzymes acetylcholinesterase (AchE) is involved in the synaptic transmission of the nerve impulse and its inhibition leads to accumulation of the neurotransmitter, acetyl choline leading to over excitation of the postsynaptic neuron. This property of the inhibitor has been exploited to develop newer insecticides against a wide range of insect pests as well as drugs effective against worms and recently a new class of neuroactive drugs against dementia or Alzheimer's disease.
The meroterpenoids are a novel family of fermentation-derived natural products. The meroterpenoids from Aspergillus terreus are naturally-occurring as terreulactones A, B, C and D and are synthesized as fermentation products. Terreulactones A, B, C and D are meroterpenoids type compounds that have mixed polyketide-terpenoid structures, which are not common in microbial metabolites. Amongst these terpenoids, terreulactone A is a sesquiterpene meroterpenoid having fused lactone skeleton in its sesquiterpene moiety (Cho et al., 2003). A literature report on terreulactone indicates its potential activity as inhibitor for acetylcholinesterase enzyme in the treatment of Alzheimer's disease. In this respect, acetyl cholinesterase inhibitors have attracted particular attention for other uses as well.
Terreulactone A can be produced from Aspergillus terreus through Solid state fermentation using wheat bran as substrate (Mi-Cho et al., 2003—J Antibiotics; 2003:56(4):344-350).
Although number of documents refer to the production of meroterpenoids by culturing different microorganisms, most of them describe fermentation processes where the nutrients are added or mixed in with the microorganism in the culture medium at the beginning of the production process. Generally, (the fixed amount of) these nutrients are therefore gradually used up during fermentation. However, at the beginning of the process, because the nutrients are at relatively high concentrations, production of desired compound is low because the microorganisms use carbon and nitrogen sources to grow, rather than to produce the drug. In such a process, the rate of production of the desired product is largely uncontrollable. Overall production levels are low because in the batch processes, nutrients are in effect supplied only once to the microorganism and so no variation (at least during production) can be made to balance growth of the biomass with production of the fermentation product.
The present disclosure overcomes the limitations associated in the prior art mentioned above.